Immune tolerance, autoimmune diseases

Immune tolerance

• Central:– negative selection during thymic education– deletion of autoreactive B-lymphocytes in bone

marrow

Positive selection in the thymus

Negative selection in the thymus

Tolerance‘Central’

Immune tolerance

• Peripheral:– Clonal deletion - elimination of autoreactive

cells by apoptosis– Clonal anergy - costimulatory signals are

lacking – Clonal ignorance - to low concentration of

antigen does not stimulate immune response– Suppression - autoreactivity is blocked by

regulatory cells

Tolerance‘Peripheral’

Regulatory T cells

• Treg cells – naturally occurring regulatory cells causing tolerance of autoantinegens. They cause active tolerance of autoantigens. Development in the thymus. Involved in inborn tolerance. Also the induction of these cells in periphery by foreign antigens seems to be possible.

• TH3 (Tr1) cells: induced in periphery. They cause acquired tolerance.

Acquired immune tolerance

• Low-zone tolerance: repeated injections of very low doses of antigen. Suppressor cells are stimulated.

• High-zone tolerance: induced by high-doses of antigen. Clonal deletion is induced.

• Oral tolerance

Mechanisms of breakage of immune tolerance

• Visualization of „hidden antigens“

• Alteration of body antigens by chemical substances, burns, necrosis

• Cross reactivity of antigens

• Excessive stimulation of the immune system, abnormal expression of HLA-II antigens.

• Defect in suppressor function of lymphocytes

Systemic lupus erythematosusRheumatoid arthritisSjogren’s syndrome PolymyositisDermatomyositisScleroderma (progressive systemic sclerosis)

Systemic autoimmune diseases

SLE

• A prototypic multi-system autoimmune and immune complex disease

• Involvement of skin, kidneys, lungs, heart blood vessels

• Immunoregulatory abnormalities• Many autoantibodies

– ANA• ds DNA• ENA

– Phospholipids

Systemic lupus etythematodes (SLE)

• Systemic autoimmune disease affecting various tissues and organs

• Many symptoms are caused by deposition of immune complexes (type-III immunopathological reaction)

• Female : male ratio is 10:1

• Usually begins in early adulthood

Systemic lupus erythematodesClinical presentation

• General: fever, malaise, loss on weight• Artralgia• Skin: butterfly rash, urticaria• Vascular: Raynaud´s phenomenon • Neurological: vasculitis, seisures, neuritis• Glomerulonephritis• Haematological: leukopenia, thrombocytopenia

anemia• Recurrent serositis

Systemic lupus etythematodes

•Butterfly rashButterfly rash

Systemic lupus etythematodes

Autoantibodies in SLE - 1

Anti-nuclear anibody (anti-nuclear factor)Indirect immunofluorescence on Hep2 cells

Staining pattern may be clinically useful

Interpretation depends on clinical story, titre and age

Sensitive but not specific

Good screening test for lupus (prevalence ~ 100%)

Positivity of antinuclear antibodies (ANA, ANF)

• SLE: 95 - 100 %

• Rheumatoid arthritis: 15 - 30 %

• Systemic scleroderma: 75 -80 %

• Autoimmune hepatitis: 20 -60 %

• Healthy persons: 0 - 4 %

• Seniors: 10 - 20 %

ANA - homogenous type

ANA – granular type

Systemic lupus erythematosus

Livedo reticularis

Systemic lupus etythematodes

Endocrine systemAutoimmune (Hasimoto’s) thyroiditisHyperthyroidism (Graves’ disease; thyrotoxicosis)Type I diabetes mellitus (insulin-dependent or juvenile diabetes)Autoimmune adrenal insufficiency (Addison’s disease)Autoimmune oophritisHermatopoietic system

Autoimmune hemolytic anemia autoimmune thrombocytopeniaAutoimmune neutropeniaNeuromuscular system

Myasthenia gravisAutoimmune polyneuritisMultiple sclerosisSkin

Pemphigus and other bullous diseasesCardiopulmonary System

Rheumatic carditisPostcardiotomy syndrome (Dressler’s syndrome)Gastrointestina tractAtrophic gastritisCrohn´s diseaseUlcerous colitisAutoimmune hepatitis

Organ-specific autoimmune diseases

Anti- parietal cells antibodies

Pernicious anemia

• Antibodies against gastric parietal cells cause atrophic gastritis.

• Decreased production of gastric juice results in dyspeptic problems.

• Also production of intrinsic factor is decreased causing disturbed resorption of vitamin B12.

• Low serum levels of vitamin B12 result in megaloblastic anemia.

Anti-receptor antibodies

• Stimulatory – – Graves disease. Antibodies against TSH-

receptors stimulate function of thyroid gland causing hypertyreosis.

• Inhibitory– Myastenia gravis. Antibodies against

acetylcholine receptor block activation of muscle in neuromuslular junction.

Treatment of autoimmune diseases

• Substitution of function of the affected organ (insulin treatment, parenteral treatment by vitamin B12….)

• Anti-inflammatory drugs

• Immunosuppressive treatment

• Tolerance induction

Systemic Immunosuppression

• High-dose steroids• Purine antagonists: Azathioprin• Alkylating agents: Cyclophosphamide• Anti-pholates: Methotrexate• Calcineurin antagonists: Cyclosporine A,

Rapamycin, Tacrolymus• Block of purins synthesis: Mycophemolate • Antilymphocytic serum• Monoclonal antobodies: anti CD3, anti CD20,

anti CD54...

Imunostimulatory drugs

• Synthetic immunostimulators: inosiplex

• Cytokines: IL-2, interferons

• Thymic hormones

• Bacterial immunomodulators: Ribomunyl, Broncho-vaxom, Luivac, Imudon, Biostim...